Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation

doi:10.1038/s41467-024-52174-z

KMS > iHuman研究所

	Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation
	Qian, Yu 1; Ma, Zhengxiong 1; Xu, Zhenmei 1; Duan, Yaning 1; Xiong, Yangjie 1; Xia, Ruixue 1; Zhu, Xinyan 1; Zhang, Zongwei 2; Tian, Xinyu 2; Yin, Han 1; Liu, Jian 1; Song, Jing 1; Lu, Yang 1; Zhang, Anqi 2; Guo, Changyou 2; Jin, Lihua 3; Kim, Woo Jae 1; Ke, Jiyuan 4; Xu, Fei5 ; Huang, Zhiwei 2; He, Yuanzheng 1
	2024-09-02
发表期刊	NATURE COMMUNICATIONS (IF:14.7[JCR-2023],16.1[5-Year])
EISSN	2041-1723
卷号	15 期号:1
发表状态	已发表
DOI	10.1038/s41467-024-52174-z
摘要	["WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/beta-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction.","Here the authors report the cryo-EM structure of Frizzeled 4 in complex with the DEP domain of Dishevelled 2. The study unveils the key mechanism of WNT signalling activation, the recruitment of dishevelled to Frizzled receptor."]
URL	查看原文
收录类别	SCI
语种	英语
资助项目	Startup Funds of HIT Center for Life Sciences["32070048","32071194"]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:001304177200002
出版者	NATURE PORTFOLIO
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/424421
专题	iHuman研究所 iHuman研究所_PI研究组_徐菲组
通讯作者	He, Yuanzheng
作者单位	1.Harbin Inst Technol, HIT Ctr Life Sci, Sch Life Sci & Technol, Lab Receptor Struct & Signaling, Harbin, Peoples R China 2.Harbin Inst Technol, Sch Life Sci & Technol, Harbin, Peoples R China 3.Northeast Forestry Univ, Harbin, Peoples R China 4.Inst Hlth & Med, Hefei Comprehens Natl Sci Ctr, Hefei, Peoples R China 5.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Qian, Yu,Ma, Zhengxiong,Xu, Zhenmei,et al. Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation[J]. NATURE COMMUNICATIONS,2024,15(1).
APA	Qian, Yu.,Ma, Zhengxiong.,Xu, Zhenmei.,Duan, Yaning.,Xiong, Yangjie.,...&He, Yuanzheng.(2024).Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation.NATURE COMMUNICATIONS,15(1).
MLA	Qian, Yu,et al."Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation".NATURE COMMUNICATIONS 15.1(2024).